Why Urea?

By Bill Peckham

I took a look at the Dialysis & Transplantation article RenalWEB highlighted over the weekend, Hemodialysis Adequacy: A Review. The editor of RenalWEB has a professional background that gave him a front row seat when the dialysis community took the wrong turn in the '80s and embraced urea removal as an important measure  of dialysis "adequacy". He could see that whatever the intentions of using urea, in practice it was misunderstood and misapplied. I'm glad I read the review but I found it frustrating because it tells the how, but not the why. Why urea?

The review begins by noting that in the early years the correct dose of dialysis was measured by determining the amount needed to keep the patient "alive and relatively asymptomatic". Aside from the apparent redundancy in this definition, it seems about right. If a dialyzor is asymptomatic then they are getting an adequate dose of dialysis. I'll go with that.

So how did we go from there, to relying on measuring the clearance of a "small electro-neutral solute"? A solute that is so easy to remove that the review notes the treatment's ability to remove urea "cannot be extrapolated to" the removal of things that actually matter. The review never says it, but the urea solute, the object of all this testing, has no bearing on the health of the person with CKD. It's odd the review doesn't mention it but urea is basically harmless. It's a marker.

Urea is such a basic and easy to remove solute that healthy kidneys easily control its level in the blood. When blood urea levels are seen to be increasing, a physician knows that there must be a serious problem. If your kidneys aren't controlling urea, there is little chance that they are controlling the blood levels of things that matter, solutes that, unlike urea, directly cause ill health. Solutes like potassium, phosphate or b2-microglobulin. Urea is a useful marker for identifying people with kidney disease and for people who use dialysis, if your urea level is high, you need to be dialyzed. But that's about the limit of urea's usefulness.

It tells you there is a problem but it is not the problem. It's as if the fire department, at the sight of smoke, would race to the scene and point their water hoses in the air to draw the smoke out of the sky. Some water would no doubt land on the fire, the problem, but not enough because they would not be focusing their resources on the real problem. Fighting severe kidney disease through urea control is like fighting a fire through smoke control, you look busy but you're missing the point. And more importantly, you're being ineffective in fighting the real battle which can be, if not won, fought to a draw.

The review leaves the big urea history questions unanswered. If urea was the solution who was defining the problem? We had a good measure - no symptoms of chronic kidney disease. Who didn't like that measure? The editor of RenalWEB highlights in the editor's comment, (very close to a blog post, just do it already), the role of corporations in making and selling ways to measure urea, but I would point to their more important role in wanting a measure like urea in the first place.

The only interests served by measuring urea are business interests. Urea is easy and inexpensive to measure. Urea is easy and inexpensive to remove. Badda bing! as they say.

Comments

[Dori Schatell]

Urea is cheap and easy to remove. It's also cheap and easy to MEASURE, which is why it was chosen in the first place. An article came out in the last month or two saying that urea actually CAN cause some harm in the body (news to me), but darned if I can find it. It's certainly not the most important molecule--if anything, multiple authors now say that it is NOT appropriate to measure just urea to assess dialysis dose, including Dr. Gotch who was one of the proponents of Kt/V in the first place! (See #5 in the conclusion of the abstract--and I've highlighted a key line in caps).

Blood Purif. 2003;21(4-5):271-81.

Daily dialysis: the long and the short of it.
Gotch FA, Levin NW.

There is considerable enthusiasm for daily hemodialysis despite the increased time commitment required of patients because of reported improvements in patient well-being, appetite and blood pressure control. To date, this therapy has been largely empirical and has been defined primarily by treatment time (t) and categorized as short daily hemodialysis (SDHD) with t about 2 h and long nocturnal hemodialysis (LNHD) with t 8-9 h. It is the authors' view that studies comparing clinical outcome with SDHD and LNHD to conventional hemodialysis (CHD) must have dialysis dosage well defined if they are to provide generalizable results. There is a broad range and overlap in the magnitude of solute removal in reported studies of SDHD, LNHD and CHD, which is illustrated here through kinetic consideration of four solutes: (1) urea; (2) inorganic phosphorus (iP); (3) beta(2)-microglobulin (beta(2)M) and (4) Na/water. The following observations can be made: (1) Patient subjective reports of increased appetite and protein intake may correlate poorly with kinetic calculation of protein catabolic rate. (2) A model of iP mass balance was developed and indicates that iP REMOVAL WITH CHD IS INADEQUATE; current SDHD is also inadequate to highly excessive depending on the dose of dialysis. (3) beta(2)M removal with SDHD is virtually the same as reported for LNHD, reflecting major differences in dialyzer membranes used. (4) The decrease in predialysis overhydration is a predictable function of the number of dialyses per week and may be one of the most important benefits of more frequent dialysis. (5) The standard K(t)/V (stdK(t)/V) provides a uniform method of dose calculation but the therapy prescription should also include consideration of the other solutes evaluated above. Copyright 2003 S. Karger AG, Basel

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Interestingly, I've been told that the reason Kt/V became the standard was because the NIH was looking for a measure of dialysis adequacy for the National Cooperative Dialysis Study, they were wowed by their INABILITY to understand the complex mathematical formula for Kt/V. Apparently, that meant it had to be really good.

[Bill Peckham]

The only things these studies have proved is that urea is an inappropriate measure of dialysis dose. If it can't distinguish between conventional 3 hour runs and conventional 4 hour runs it's a bad measure. These studies really are saying more about the measure than the dialysis.

Given high enough exposure, like smoke, it wouldn't surprise me too much if urea caused some direct symptoms but I would be interested in understanding how its effect was isolated.

I think number four shows the way: 4) The decrease in predialysis overhydration is a predictable function of the number of dialyses per week and may be one of the most important benefits of more frequent dialysis.

Water is an easy to remove molecule too. If we have to have a cheap and easy to measure molecule, we should use water and the dialyzor's level of predialysis overhydration. Maybe that sounds complicated in Latin.

[Dori Schatell]

I couldn't agree more. Urea may be cheap and easy to measure, but its ease of diffusion through cell walls made it a bad choice regardless. And the whole idea that the body is a machine, and you can measure a chemical to see how dialysis is working--instead of ASKING the person how they feel and whether s/he can function was wrong-headed from the start. NIH forgot that there were PEOPLE attached to those machines, and the insistence on numbers has been a mistake from the beginning. IMHO, Dr. Scribner was much more on track.